Activation of the Acquired Immune Response Reduces Coupled Bone Formation in Response to a Periodontal Pathogen

Abstract

Osteoimmunolgy involves the interaction of the immune system with skeletal elements. This interaction can lead to the formation of osseous lesions. To investigate how the acquired immune response could contribute to osteolytic lesions, we injected the periodontal pathogen Porphyromonas gingivalis adjacent to calvarial bone with or without prior immunization against the bacterium. Activation of the acquired immune response increased osteoclastogenesis and decreased coupled bone formation. The latter was accompanied by an increase in nuclear translocation of the transcription factor FOXO1 in vivo, increased apoptosis of bone-lining cells measured by the TUNEL assay and number of activated caspase-3 positive cells and a decrease in bone lining cell density. Further studies were conducted with MC3T3 osteoblastic cells. Apoptosis and increased FOXO1 DNA binding activity were induced when a combination of cytokines was tested, IL-␤, TNF-␣, and IFN-␥. Knockdown of FOXO1 by small interfering RNA significantly reduced cytokine stimulated apoptosis, cleaved caspase-3/7 activity and decreased mRNA levels of the proapoptotic genes, TNF-␣, FADD, and caspase-3, -8, and -9. These results indicate that activation of the acquired immunity by a periodontal pathogen reduces the coupling of bone formation and resorption. This may occur by enhancing bone lining cell apoptosis through a mechanism that involves increased FOXO1 activation. These studies give insight into inflammatory bone diseases such as periodontal disease and arthritis were the formation of lytic lesions occurs in conjunction with deficient bone formation and activation of an acquired immune response.

Infection and inflammatory mechanisms

“…TNF-a up-regulates the production IL-1b and IL-6 (Okada et al 1997, Dinarello 2000, Wajant et al 2003, Kwan Tat et al 2004, Garlet et al 2007, Musacchio et al 2009). TNF-a is also correlated with extracellular matrix degradation and bone resorption through actions promoting secretion of MMPs and RANKL (Graves & Cochran 2003, Garlet et al 2004) and coupled bone formation (Behl et al 2008). Accordingly, TNFa in circulation significantly impacts systemic inflammation and associated systemic conditions (CRP and CVD, obesity, Type 2 diabetes).…”

The Role of Chemokines and Cytokines in the Pathogenesis of Periodontal and Periapical Lesions: Current Concepts

“…Accordingly, the blockade of RANKL by OPG leads to a reduction of alveolar bone loss throughout experimental PD in mice (Jin et al, 2007). Appropriately, the coupled bone formation, which takes place under homeostatic conditions (Parfitt, 1982), seems to contribute to the conventional increased bone resorption in overall bone loss in PD (Behl et al, 2008). It has long been assumed that the host defense against microbial invasion and subsequent tissue destruction involves both innate and adaptive immunity cytokines.…”

“…Curiously, the individual absence of innate immunity cytokines attenuates inflammatory bone loss; however their simultaneous inhibition results in more effective protection leading to almost complete remission of bone loss rate (Sartori et al, 2009, Graves & Cochran, 2003. In addition to a direct action toward bone resorption, innate immune cytokines also interfere with the coupled bone formation process (Behl et al, 2008). In fact, recent studies confirmed the early hypothesis that proinflammatory cytokines inhibit osteogenic differentiation (Ding et al, 2009, Lacey et al, 2009), and also demonstrate that activation of TLRs in osteoblasts induces the production of osteoclastogenic cytokines (Bar-Shavit, 2008).…”

Inflammatory Cytokines and the Pathogenesis of Periodontal Disease

“…The local cellular effects of TNF-α include the adhesion of polymorph nuclear leukocytes (PMNs) to endothelial cells, degranulation of PMNs, activation of phagocytosis and intercellular adhesion molecule (ICAM) -1 expression. The amount of TNF-α was demonstrated at high levels in gingival crevicular fluid and diseased periodontal tissues [8,16] and experimental studies have shown a central role for TNF-α in alveolar bone resorption [31,32]. …”